ASH News Daily 2017 - Issue 2 - A-2

ASH NEWS DAILY

Page A-2

Sunday, December 10, 2017

ASH News Daily
2017 Editorial Board
Editor

Saad Zafar
Usmani, MD,
FACP,
Levine Cancer
Institute,
Charlotte, NC
@szusmani
Authors

Farrukh
Awan, MD,
The Ohio
State
University,
Columbus,
OH
@awandoc
Mehdi
Hamadani,
MD, Medical
College of
Wisconsin,
Milwaukee, WI
@medihumandani
Lynn
Lederman,
PhD,
Mamaroneck,
NY
@lynnelederman
Hugh Young
Rienhoff, MD,
MyDaughters
DNA.org,
Imago
BioSciences,
San Carlos, CA
Nina Shah,
MD,
University
of California,
San Francisco,
CA
@ninashah33
Binod Dhakal, MD, MS, Medical College of Wisconsin; and
Peter Forsberg, MD, University of Colorado, are serving
as a Junior Authors this year.
©2017 by the American Society of
Hematology
All materials contained in this
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copyright laws and may not be
used, reproduced, or otherwise
exploited in any manner without
the expressed prior permission of
ASH News Daily.
Contributing authors have declared
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or in potentially competing
products, regardless of the dollar
amount. Any such financial interest
is noted with the respective articles.

IMMUNE DISORDERS

Surmounting the Wrath of the Bad Genes!
By Binod dhakal Md, MS, and
Mehdi haMadani, Md

still have vivid memories of Jack
- a 17-year-old boy diagnosed
with common variable immunodeficiency (CVID) at an early age
whom I took care of multiple times
during my internship. His mother,
accompanying him on almost every visit, once shared with me her
poignant tale of sudden disasters
at home, including the frequent
infections, visits to the emergency
department, and the ensuing breakdown of their emotional, biological, and familial order. Their story
epitomizes the suffering of patients
with primary immune deficiencies
disorders (PIDs) and their families.
Since the first description of the
link between agammaglobulinemia and recurrent infections in
early 1950s by Col. Ogden Bruton
(regarded by many as the father of
clinical immunology), significant
advances have been made in the
understanding of PIDs. Primary
antibody deficiencies (PADs) are
the most common PIDs in humans,
and this year's meeting dedicated
a session chaired by Dr. Marina
Cavazzana of Hôpital NeckerEnfants Malades Paris on PADs,

FDA

«« From Page A-1

certain types of NHL. Both approvals are hailed as an important
milestone that brings this innovative class of genetically modified
therapies to patients where options
are very limited. Dr. Pazdur said,
"For both applications, the reviews
were completed using a coordinated, cross-agency approach. The
clinical reviews were conducted by
the FDA's OCE, while the Center
for Biologics Evaluation and Research conducted all other aspects
of review and made the final product approval determinations." Both
drugs, however, come with a hefty
price tag; Yescarta may be nominally lower than Kymriah and could
present a number of financial, toxological, and logistical challenges
that need to be addressed.
This year, the FDA also approved
inotuzumab ozagamicin for adults
with relapsed and refractory B cell
ALL. The approval is an important
step for patients for whom options
are very limited. For NHL, two
other drugs were approved: copanlisib, a new PI3K inhibitor for
relapsed follicular lymphoma, and
acalabrutinib for mantle cell lymphoma patients who have received

autoimmune-associated PIDs, and
newborn screening challenges in
the current era.
Dr. Anne Durandy, also of Hôpital Necker-Enfants Malades in
Paris, discussed the recent scientific discoveries made in PADs. She
highlighted how the use of novel
approaches such as whole-genome
sequencing and mouse genetic engineering has identified new genes
that are involved in the pathogenesis of PADs. Her talk was focused
on two signaling pathways, which
must be precisely regulated during
immune response, especially in B
cells. The first was the PI3K pathway where a loss of function results in agammaglobulinemia and
gain of function to activated PI3K
delta syndrome (APDS). The other
pathway was the NF-kB pathway
where loss of function leads to CID
or CVID, whereas gain of function
leads to a different B cell defect.
Dr. Troy Torgerson of Seattle
Children's Hospital highlighted the
flip side of immune deficiency -
autoimmunity, a cruel paradox in
patients whose immune systems are
incapable of responding to foreign
antigens, can mount robust pathogenic responses to self-antigen. He
focused on the current therapeutic

approaches used to treat disorders
associated with dysfunction in the
T-regulatory cells (Tregs) and insights gained by characterizing
these PIDs into Tregs development
and function.
Dr. Jennifer Puck of the University of California San Francisco
discussed the challenges of newborn screening for PIDs in the era
of next-generation sequencing.
She presented examples of diagnoses made for infants discovered to have T cell insufficiency
by newborn screening. She also
highlighted how variants found by
deep sequencing were proven to
be disease-causing in vitro and in
vivo studies. Genomic sequencing
is a powerful diagnostic modality
and provides an opportunity to
detect conditions like PIDs before
development, but many technical,
clinical, ethical, and societal challenges should be addressed before
wide deployment. Both the healthcare providers and public health
entities must be good stewards of
this technology, ensuring ethical
standards and evidence based outcomes.

one prior therapy. All these approvals will be discussed in detail at the
meeting.
On the expedited programs and
its implications, Dr. Pazdur states,
"Under the FDA OCE, established
[est. in January 2017], we are able to
bring together experts from across
the FDA to expedite the development of medical oncology and malignant hematology products, including biologics and devices." He
underscored that the OCE's role
is to conduct the clinical review of
applications for products undergoing expedited review such as those
granted breakthrough-therapy designation, accelerated approval, or
priority review. "In this way," he
said, "we can mobilize our resources
to promote the more rapid completion of reviews for drugs for which
there is an urgent medical need."
All these new drugs come with
significant cost and with minimal
data on the quality of life. Cost is
not within FDA's purview, but
under the 21st Century Cures Act
enacted in 2016, the FDA is working to incorporate patient-reported
outcomes (PRO) data assessing
symptoms and function where appropriate. The OCE is striving to
identify rigorous methods to assess the patient experience to com-

plement efficacy and safety data.
Dr. Padzur adds, "An important
challenge for the academic and
drug development community is
agreement on standard methods
to analyze and interpret PRO data,
and we are actively partnering
with stakeholders to address these
challenges."
All the new approvals, specifically these two gene therapies, mark
a milestone in the development of
new therapeutics. It is a little too early to say whether they are absolute
game-changers; only time will tell!

Dr. Dhakal and Dr. Hamadani indicated no relevant conflicts of interest.

Just Added
Special Session on the Hematologic Response to Mass Casualty Radiological Disasters
Sunday, 9:30-11:00 a.m.,
Room B401-B402, Georgia
World Congress Center
Special Networking Session
on Systems-Based Hematology
Sunday,
4:30-6:30
p.m.,
Room B401-B402, Georgia
World Congress Center

http://www.DNA.org

Table of Contents for the Digital Edition of ASH News Daily 2017 - Issue 2